Prostate tumor cell-derived IL-1β induces an inflammatory phenotype in bone marrow adipocytes and reduces sensitivity to docetaxel via lipolysis-dependent mechanisms.

Adipocyte-tumor cell cross-talk is one of the critical mediators of tumor progression and an emerging facilitator of therapy evasion. Tumor cells that metastasize to adipocyte-rich bone marrow take advantage of the interplay between metabolic and inflammatory pathways to activate prosurvival mechanisms that allow them to thrive and escape therapy. Using in vitro and in vivo models of marrow adiposity, we demonstrate that metastatic prostate carcinoma cells engage bone marrow adipocytes in a functional cross-talk that promotes IL1 beta expression in tumor cells. Tumor-supplied IL1 beta contributes to adipocyte lipolysis and regulates a proinflammatory phenotype in adipocytes via upregulation of COX-2 and MCP-1. We further show that the enhanced activity of the IL1 beta/COX-2/MCP-1 axis and a resulting increase in PGE(2) production by adipocytes coincide with augmented hypoxia signaling and activation of prosurvival pathways in tumor cells, revealing a potential mechanism of chemoresistance. The major consequence of this interplay is the reduced response of prostate cancer cells to docetaxel, a phenomenon sensitive to the inhibition of lipolysis.